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Antagonist activity of α‐substituted 4‐carboxyphenylglycine analogues at group I metabotropic glutamate receptors expressed in CHO cells
Author(s) -
Doherty A J,
Collingridge G L,
Jane D E
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702297
Subject(s) - metabotropic receptor , metabotropic glutamate receptor , metabotropic glutamate receptor 1 , metabotropic glutamate receptor 5 , pharmacology , receptor , antagonism , metabotropic glutamate receptor 2 , metabotropic glutamate receptor 7 , antagonist , agonist , competitive antagonist , metabotropic glutamate receptor 4 , glutamate receptor , metabotropic glutamate receptor 6 , biology , chemistry , biochemistry
We have investigated the antagonist properties of 6 α‐substituted phenylglycine analogues based on the structure of 4‐carboxyphenylglycine (4‐CPG) for group I metabotropic glutamate receptors (mGlu 1α and mGlu 5a ) permanently expressed in CHO cells. (S)‐4‐CPG and (S)‐MCPG were the most selective mGlu 1α receptor antagonists. Longer chain α‐carbon substitutions resulted in a progressive loss of antagonist affinity at mGlu 1α receptors but not at mGlu 5a receptors. Thus mGlu 1α receptor antagonists require small aliphatic groups at the α‐position. α‐cyclopropyl‐4‐CPG showed a tendency towards mGlu 5a selectivity, suggesting that bulky groups at this position may favour mGlu 5a receptor antagonism. We demonstrate that the mGlu 5a receptor displays agonist‐dependent antagonism. L ‐glutamate‐induced Ca 2+ release in mGlu 5a receptor expressing cells was more susceptible to antagonism by cyclic α‐carbon derivatives than (S)‐3,5‐dihydroxyphenylglycine (DHPG)‐induced Ca 2+ release in the same cell line. The data presented suggests that mGlu 1α and mGlu 5a receptors have different steric and/or conformational requirements for the binding of antagonists and different amino acids which could interact with agonists. These phenylglycine analogues could provide leads for the development of subtype selective antagonists.British Journal of Pharmacology (1999) 126 , 205–210; doi: 10.1038/sj.bjp.0702297